There is currently no cure for any autism spectrum disorder, and the current pharmacological treatments have had limited success. Finding treatments for autism has proven challenging for two major reasons. First, defects in multiple genes increase risk for autism, which makes it difficult to study and identify effective treatments. Second, drug screening in neurons, which are non-dividing cells, poses immense technical challenges. Benjamin Philpot and his colleagues at the University of North Carolina have sought to overcome these challenges by developing a novel neuronal drug screen to identify small-molecule compounds for treating autism caused by dysregulation of a single gene, UBE3A.

The loss of UBE3A causes a severe intellectual disability called Angelman syndrome, an autism spectrum disorder. Some forms of autism may also be caused by having multiple gene copies of UBE3A. The labs of Philpot, Mark Zylka and Bryan Roth developed a high-throughput method of finding small-molecule compounds that alter the expression of UBE3A. Using this screen, the researchers discovered that topoisomerase inhibitors can unsilence a dormant gene copy of UBE3A. Hence, this class of drugs serves as a potential treatment for Angelman syndrome. Some topoisomerase inhibitors are already approved by the U.S. Food and Drug Administration to treat cancer.

The researchers are currently exploring approaches to deliver topoisomerase inhibitors effectively and safely to the brain, in addition to exploring alternative approaches for regulating UBE3A based on the mechanistic insights they gained from their research. The research also provides a proof of concept that small-molecule compounds can alter the expression of UBE3A or other autism genes, and this finding has inspired similar approaches in Philpot’s lab and others to screen for new autism therapeutics.